DE68914604T2 - Wound dressing. - Google Patents

Description

This invention relates to wound dressings. More particularly, it relates to wound dressings having two layers, one being a polyurethane resin film with good moisture permeability and the other being a layer of a biopolymer material that acts as an artificial skin for the growth of tissue cells.

Some properties necessary for wound dressings are: 1) adhesion, 2) flexibility, 3) durability, 4) ease of handling, 5) storage, 6) sterile filtration, 7) compatibility with cells, 8) hemostasis, and 9) water vapor permeability.

Although conventional wound dressings meet some of these properties, they do not meet all of them.

For example, a sheet made of only a biopolymer material essentially lacks flexibility and sterile filtration effect due to poor flexibility, the sheet lacks adhesion to a wound surface, and some sheets essentially lack preservative properties and are not easy to handle. In case of poor sterile filtration effect, it is necessary to use a cream, which contains an antibacterial agent, to the affected part every two to three days. This is very tedious for the nurse and very painful for the patient.

On the other hand, a laminated layer made of a layer of biopolymer material and a silicone film has poor water vapor permeability and exudate is stored dangerously under the dressing. It is possible to make such a laminated layer thinner to try to overcome this disadvantage, but a thinner layer is not easy to deal with in practice.

Generally, in the first stage of using a wound dressing, a lot of exudate is generated. A laminated sheet may have holes mechanically created in it to allow the exudate to drain, but when the generation of exudate becomes low, the holes become blocked by solidification of the exudate. Therefore, it is necessary that the sheet has good water vapor permeability after the holes are blocked. For example, in the case of a burn, the water loss by evaporation from a wound is 300 g H₂O/m² x 24 hours for a first degree burn, 4300 g H₂O/m² x 24 hours for a second degree burn, and 3400 g H₂O/m² x 24 hours for a third degree burn (L.O. Lamke Burns. 3, pp. 159-165).

For example, a silicone resin film used as a wound dressing does not have sufficient water vapor permeability (it has a low water vapor permeability of 1000 - 1700 H₂O/m² x 24 hours). Therefore, no wound dressing has been available to date that has sufficient water vapor permeability for the large amount of evaporation mentioned above in addition to good flexibility, durability and the possibility of easy handling.

EP-A-184 233 discloses a drug-distributing wound dressing comprising a polyurethane matrix which is the reaction product of (A) an isocyanate-terminated prepolymer formed by reaction of isophorone diisocyanate and a macroglycol, and (13) a monomer containing hydroxyl and vinyl groups.

DE-A-2 631 909 discloses a multilayer membrane for use as a synthetic skin comprising a first layer formed from a material which does not induce an immune reaction and is insoluble and non-degradable in the presence of body fluids and/or body enzymes, and a second layer formed from a non-toxic material which controls the moisture flux of the total membrane to about 0.1 to 1 mg/cm²/hour.

US-A-3,800,792 discloses a surgical dressing comprising a thicker layer of a collagen-pressed foam film to which has been laminated without any adhesive a thin continuous layer of an inert polymeric material such as polyurethane, and which has a slightly higher water vapor transmission rate than normal skin.

The present inventors made investigations to solve the problems of conventional sheets consisting only of biopolymer materials and a laminate layer thereof, that is, to provide a wound dressing which is excellent in 1) adhesion, 2) flexibility, 3) durability, 4) ease of handling, 5) preservability, 6) sterile filtration effect, 7) compatibility with cells, 8) hemostasis and 9) water vapor permeability.

The present invention provides a wound dressing comprising a sheet of a biopolymer material and a film of a polyurethane resin having a water vapor permeability of 2000 g/m2 x 24 hours or more, the polyurethane resin being obtainable by reacting a diisocyanate and a random copolymer of tetrahydrofuran and ethylene oxide to prepare a urethane prepolymer and extending the molecular chain of the prepolymer using a chain extender, said random copolymer containing 20 to 80% by weight of ethylene oxide units in its molecular chain and having a number average molecular weight of 800 to 3000.

The polyurethane resin used for the polyurethane film in the present invention is obtainable by using a random copolymer of tetrahydrofuran (hereinafter referred to as "THF") and ethylene oxide (hereinafter referred to as "EO") as a polyol component. This copolymer can be synthesized by ring-opening copolymerization of THF and EO at a temperature of 20 to 50°C in the presence of an initiator, for example, water, short-chain diols such as ethylene glycol and 1,4-butanediol, and a Lewis acid catalyst such as boron trifluoride ethyl etherate.

The content of EO units in the random copolymer of THF and EO is 20 to 80 wt.%, preferably 30 to 70 wt.%, particularly preferably 40 to 60 wt.%, based on the weight of the copolymer, in order to reduce swelling due to water absorption and deterioration of the physical properties of the polyurethane film. The number average molecular weight of the random copolymer of THF and EO is 800 to 3000. If the number average molecular weight is less than 800, the polyurethane film becomes hard, and if it is more than 3000, it shows strong sticky adhesion and increased swelling by water absorption. In order to provide excellent film properties, the number average molecular weight is preferably 1000 to 2500.

A mixture of the random copolymer of THF and EO and polytetramethylene ether glycol (hereinafter referred to as "PTMG") may also be used if necessary. In this case, the number average molecular weight of the added PTMG is 800 to 3000 and that of the polyol mixture is 800 to 3000, preferably 1000 to 2500, in order to provide well-balanced properties. It is not a disadvantage in the present invention if the above random copolymer of THF and EO includes a partial block copolymer structure in its molecular chain.

A copolymer of THF and EO generally includes a copolymer synthesized by addition reaction of EO and PTMG obtained from ring-opening polymerization of THF, or by addition reaction of THF and polyethylene glycol (hereinafter referred to as "PEG") obtained by ring-opening polymerization of EO.

However, a polyurethane produced from these block copolymers is not suitable for practical use because the swelling by water absorption increases significantly with an increase in the EO content, similar to the case of using a mixture of PTMG and PEG, due to the inclusion of the highly hydrophilic long homopolymer chains of EO in the molecular chain.

When the above random copolymer of THF and EO or the mixture of this random copolymer and PTMG is used as a polyol component of a polyurethane, the polyurethane film has good water vapor permeability as compared to the above block copolymer of THF and EO or a mixture of PTMG and PEG used together, although the increase in water absorption with increase in the content of EO units is small.

In order to obtain the polyurethane resin used in the present invention, a method is generally employed in which, after obtaining a urethane prepolymer having an isocyanate group at the end of its molecular chain by reacting the above specific polyol component and an excess equivalent of diisocyanate at 70 to 120°C, the chain of the urethane prepolymer is extended by a chain extender at 20 to 100°C in an organic solvent.

The equivalent ratio of diisocyanate and polyol component in the urethane prepolymer is usually 1.5 to 6:1 and preferably 1.8 to 4.5:1 to provide good physical properties and water vapor permeability. The isocyanates used are, for example, aromatic diisocyanates such as 4,4'-diphenylmethane diisocyanate, 2,4- and 2,6-tolylene diisocyanate, 1,5-naphthalene diisocyanate and m- and p-phenylene diisocyanate, alicyclic diisocyanates such as isophorone diisocyanate, 4,4'-dicyclohexylmethane diisocyanate, 1,4-cyclohexylene diisocyanate and hydrogenated tolylene diisocyanate and aliphatic diisocyanates such as hexamethylene diisocyanate.

Among these, the alicyclic diisocyanates are preferred due to their resistance to yellowing and good mechanical properties. These diisocyanates are generally used individually, but two or more diisocyanates may be used together. Among the alicyclic diisocyanates, 4,4'-dicyclohexylmethane diisocyanate is particularly preferred due to its good balance of mechanical properties and water vapor permeability of the film formed.

The chain extenders used are, for example, low molecular weight diols such as ethylene glycol, propylene glycol, diethylene glycol, 1,4-butanediol and 1,6-hexanediol, aliphatic diamines such as ethylenediamine, 1,2-propanediamine, tetramethylenediamine and hexamethylenediamine, alicyclic diamines such as isophoronediamine, 4,4'-dicyclohexylmethanediamine, 3,3'-dimethyl-4,4'-dicyclohexylmethanediamine and 1,4-cyclohexylenediamine, hydrazine hydrate and water.

Among these compounds, alicyclic diamines are most preferred due to the good stability of the polyurethane solution and good heat resistance of the film formed. These compounds may be used singly, or two or more may be used together. The above low molecular weight diols may be used together in such an amount that the mechanical properties and heat resistance of the film produced are not too much lowered. Among the alicyclic diamines, isophoronediamine is most preferred due to the stability of the solution and the good balance of various properties of the film.

Organic solvents with a strong dissolving power, such as dimethylformamide, dimethylacetamide and dimethyl sulfoxide, are suitable for the synthesis of the Polyurethanes. These solvents can be used individually and can also be used together with one or more solvents selected from aromatic compounds such as toluene and xylene, ketones such as methyl ethyl ketone, acetone and cyclohexanone, esters such as ethyl acetate and butyl acetate, ethers such as tetrahydrofuran and dioxane, and alcohols such as methanol and 2-propanol.

The polyurethane resin obtained as described above preferably contains the ethylene oxide unit in an amount of 15 to 60% by weight based on the total weight of the polyurethane. If the content of ethylene oxide units is less than 15% by weight, the water vapor permeability of the film is insufficient, and if the content of ethylene oxide units is higher than 60% by weight, considerable dimensional changes and deterioration of physical properties by swelling occur when water is absorbed.

If necessary, a catalyst generally used to promote the urethane formation reaction, for example, tertiary amines such as triethylenediamine and organic tin compounds such as dibutyltin dilaurate, may be used in the reaction.

The polyurethane may be previously incorporated with one or more antioxidants of the hindered phenol type, benzophenone type or benzotriazole type, ultraviolet absorbing agents or hindered amine stabilizers to provide better durability. In this case, each additive may be used in an amount of 0.05 to 3% by weight based on the weight of the polyurethane solids, and preferably in an amount of 0.2 to 1% by weight to obtain better durability. In polyurethane, the above hindered amine stabilizers are particularly effective in preventing deterioration due to oxidation in sterilization treatment and deterioration of properties due to hydrolysis.

Either porous or non-porous polyurethane films are also available. It is known that polyurethane films with high water vapor permeability are obtained when the film is made porous. Examples of manufacturing processes for obtaining porous polyurethane films are:

(1) A wet film forming process in which a solution of polyurethane resins is coated on a support and soluble substances such as solvents are extracted into a coagulation bath; and

(2) a method in which a water-in-oil emulsion is coated on a carrier and the porous membrane is obtained after drying by heating.

The non-porous polyurethane films can be obtained by a dry film forming method in which a solution of a polyurethane resin is coated on a support or peelable paper and dried by heating. According to this method, films can be obtained which have stable and reproducible water vapor permeability and also have sufficiently practical strength, tensile strength and durability even when used as a single film.

When dry film formation is carried out, the supports used are not limited, but polyethylene or Polypropylene films, release papers or textiles coated with fluorine- or silicon-containing release agents are preferably used. The above release papers preferably have a uniform thickness because the degree of water vapor permeability of the polyurethane films is in reciprocal relation to the film thickness. The coating method is not particularly limited; either a knife coater or a roll coater can be used. The drying temperature is arbitrarily set according to the capacity of the drying instrument, but it is necessary to select the temperature range so that insufficient drying or rapid solvent removal does not occur. The temperature is preferably 60 to 130°C.

The thickness of the polyurethane film is usually 10 to 200 µm, preferably 10 to 80 µm. If the thickness is less than 10 µm, pinholes are easily formed during drawing, and the formed films are not easy to handle because the films easily stick together. If the thickness is over 80 µm, it becomes difficult to obtain sufficient water vapor permeability. The thickness dependence of the water vapor permeability is small in the polyurethane films used in the present invention as compared with other urethane-type films.

The polyurethane films used in the present invention have a high water vapor permeability which is 2000 g/m² x 24 hours or more (as measured by JIS Z 0208), preferably 3000 g/m² x 24 hours or more for non-porous films having a thickness of 10 to 80 µm. A film having a water vapor permeability of less than 2000 g/m² x 24 hours causes discomfort due to the water vapor generated when the skin is covered with the film. The 100% modulus of the The modulus of the polyurethane film used in the present invention is 20 kg/cm² or more, preferably 30 kg/cm² or more. If the 100% modulus is less than 20 kg/cm², the films are likely to stick together. On the other hand, if it is more than 80 kg/cm², they are likely to lack flexibility and have lower water vapor permeability.

Since there is a lot of exudation of body fluid in the first stage of using a wound dressing, if the wound dressing has insufficient water vapor permeability, the healing of a wound is slow due to the inhibition of the adhesion of the wound dressing to the wound by retaining the exudate between the wound and the wound dressing.

To prevent slow healing, it is preferable to provide holes in the wound dressing, especially in the polyurethane film, to allow exudate to drain from a first-stage wound.

It is sufficient that the exudate drains through the holes from a wound in the early stage. For this purpose, the diameter of the holes is about 0.01 to 1 mm, preferably about 0.1 to 0.7 mm, and the number of holes is about 2 to 50/cm², preferably about 5 to 20/cm².

The holes are formed by piercing needles into the film or by punching.

The holes can be blocked after the passage of exudate in the early stage. It is more preferable that the holes are blocked after the exudate has passed to prevent the entry of bacteria. Therefore, it is also preferable to form slits that are easy to instead of holes. The slits can be made in shapes such as "+", "V", "L", "U", "I" and "-". The exudate can drain through the slits and after that the slits can be hermetically sealed to prevent the entry of bacteria.

When holes are provided that are always open by needles, it is preferable to preheat the needles to the melting point of the polyurethane film or above. In this case, it is preferable to add an antibacterial agent to the polyurethane film and the layer of biopolymer material to prevent the penetration of bacteria. When antibacterial agents are used, the diameter of the holes is preferably within the diameter of the inhibition range of the antibacterial agent used.

As the biopolymer material usable in the present invention, there may be mentioned, for example, collagen, gelatin, alginic acid, chitin, chitosan, fibrin, dextran and polyamino acid. Of the above, collagen and chitosan are particularly preferably used. The collagen may include, for example, succinyl collagen, acetyl collagen and methyl collagen.

It is particularly preferred to use atelocollagen obtained by removing non-helical parts at the end of the molecule by treatment with a protease other than collagenase, since it is almost neutral and biocompatible.

Chitosan is also preferably used. Chitosan is preferably a substance that is formed by the action of Chitin deacetylated with concentrated alkalis is used. The degree of deacetylation is 40% or more, preferably 50% or more.

It is also preferred that N-acylchitosan obtained by reacting chitosan with a carboxylic acid anhydride is used. A mixture of collagen and chitosan can also be used.

A method for forming a layer of biopolymeric material is exemplified below:

A solution, dispersion or gel of collagens and/or chitosans is prepared. Then, it is formed into a sponge-like sheet by freeze-drying or a film by removing the solvents after flow casting on a flat plate. The thickness of the biopolymer material sheet is usually 10 to 100 µm, preferably 10 to 80 µm. When laminate sheets are formed with a polyurethane film, either a single sheet or two or more sheets of biopolymer material may be stacked for use. It is also possible to obtain a wound dressing having an antibacterial effect by incorporating antibacterial agents. For incorporating antibacterial agents into the wound dressing of the present invention, a biopolymer material sheet or a polyurethane film containing a given amount of an antibacterial agent may be used. A polyurethane film containing a given amount of an antibacterial agent may also be provided between the polyurethane film and the layer of biopolymeric material, thereby forming a three-layer wound dressing of polyurethane film/polyurethane film with antibacterial agent/layer of biopolymeric material. Examples of antibacterial agents are Sulfa drugs, cephalosporins, penicillins and nalidixic acid and derivatives thereof.

The amount of the antibacterial agent used depends on the type of antibacterial agent used. However, it is usually 0.001 to 10% by weight based on the weight of the polyurethane film or the weight of the layer of biopolymer material.

The polyurethane film containing the antibacterial agent can be obtained by dissolving a polyurethane resin and an antibacterial agent in a solvent capable of dissolving both the resin and the agent, thoroughly mixing the solution and then forming it into a film.

As solvents for dissolving both the resin and the agent, alcohols are usually used. Of alcohols, those having 5 or less carbon atoms and a boiling point of not more than 120°C are preferred. Methanol, ethanol, n-propanol, 2-propanol, n-butanol, sec-butanol, isobutanol and 3-pentanol may be particularly mentioned.

Examples of methods for lamination are a method in which the biopolymer material layer is laminated on the polyurethane film after swelling the surface of the polyurethane film with a solvent that can moderately swell the film surface, for example, alcohols such as methanol, and dried, and a method in which the polyurethane film is laminated on the biopolymer material layer after absorbing the above-mentioned described solvent in the layer, causing the surface of the polyurethane film to swell and dry.

The wound dressing thus obtained is used by bringing the surface of the sheet of biopolymer material into contact with a wound. With the healing of a wound, the biopolymer material is absorbed into the living tissue and therefore the polyurethane film can be easily peeled off from the sheet without damaging the surface of a wound after healing.

The present invention is further illustrated in the following examples.

Production examples 1 to 4

Preparation of THF-EO random copolymer

Random copolymerization of THF and EO was carried out in an autoclave for the compositions shown in Table 1 under the conditions of normal pressure and a temperature of 30°C. Ethylene glycol was used as an initiator and boron trifluoride ethyl etherate as an acid catalyst. After completion of the copolymerization, the acid catalyst in the product was neutralized with alkali, the precipitates were filtered off and then dried by blowing dry nitrogen gas at 100°C.

Four random copolymers of THF and EO (hereinafter referred to as "polyol"), A, B, C and D were obtained. They are all colorless and transparent liquids, where the number average molecular weight and EO content are shown in Table 1.

The number average molecular weight is calculated from the OH value and the EO content from the amounts of EO added. Table 1 Number of preparation examples (comparative example) Composition of the polyols Components of the polyol (parts by weight) Number average molecular weight EO content (% by weight) Ethylene glycol Boron trifluoride ethyl etherate

Production examples 5 to 8 Production of a urethane film a) Preparation of a polyurethane solution

A urethane prepolymer having an isocyanate group at the end of its molecular chain was prepared by reacting 4,4'-dicyclohexylmethane diisocyanate and each of the polyols A, B, C and D used in Preparation Examples 1 to 4 were obtained in the compositions shown in Table 2 in a flask under a dry nitrogen atmosphere at 100°C for 6 hours. Thereafter, a chain extension reaction was carried out for each of the above prepolymers in dimethylformamide using isophoronediamine as a chain extender at 30°C for 2 hours. Polyurethane solutions each of which was colorless, transparent and viscous were obtained. The solid content of each solution was 25% by weight. The viscosities of the solutions at 25°C were 35,000 cps, 20,000 cps, 15,000 cps and 16,000 cps, respectively.

b) Formation of a polyurethane film

Polyurethane resin was precipitated by dropping each of the above solutions into water. After filtering and drying the solid polyurethane, methanol solutions containing 15% by weight of polyurethane resin were prepared. Silver sulfadiazine as an antibacterial agent was then added in an amount of 30% by weight based on the weight of the polyurethane resin and the mixture was stirred to make it uniform.

Each polyurethane solution containing the antibacterial agent was flow cast on glass plates provided with a spacer, expanded to uniform thickness by a glass rod, and dried at 80ºC for a whole day and night. Colorless and transparent polyurethane films were obtained by a dry process. The film thickness was controlled to about 30 µm by the spacer. To study the dependence of water vapor permeability on film thickness, films of different thicknesses were range of 10 to 100 µm. The resulting films were stored in a thermohygrostat at 23ºC and 60% relative humidity.

Tests of the properties of the polyurethane films were carried out as follows:

Properties test of the polyurethane film (Measurement of dimensional increase due to water absorption)

The dimensional increase due to water absorption was calculated on the measured values before and after water absorption by immersing polyurethane films of 50 mm x 50 mm in water at 23ºC for 24 hours.

(Measurement of water vapor permeability)

The water vapor permeability was obtained from the measurement of weight using a cup for water vapor permeability measurement under the conditions of 40ºC and 90% RH according to JIS Z-0208.

(Oxidation resistance test)

The influence on the mechanical properties by oxidative deterioration was checked by irradiation with gamma rays with an exposure dose of 2.5 Mrad at a dose rate of 106 rad/hour in air, assuming a sterilization treatment by irradiation.

(Hydrolysis resistance test)

The hydrolysis resistance was determined by measuring the mechanical properties after exposure to Polyurethane films were evaluated in an atmosphere of 70ºC and 95% RH for 3 weeks.

Manufacturing example 9 Production of a polyurethane film

A hindered amine type stabilizer, Tinuvin 622 LD (sold by Ciba-Geigy Co.) was added to the polyurethane solution obtained in Preparation Example 6 in an amount of 0.5 wt% based on the weight of the polyurethane contained in the solution. Then, a polyurethane film was prepared by the same method as in Preparation Example 6 and tests were carried out.

As shown in Table 4, the properties of the polyurethane film were remarkably improved in comparison with the film of Preparation Example 6 not containing Tinuvin 622 LD, such as oxidative deterioration upon irradiation with gamma rays and deterioration of mechanical properties by hydrolysis. Table 2 Number of the production example (comparative example) Composition of the polyurethane (parts by weight) Additives Polyol 4,4'-dicyclohexylmethanediisocyanate Isophoronediamine Tinuvin 622LD 0.5% by weight based on polyurethane.

Production examples 10 to 13 Production of a polyurethane film

Polyurethane solutions were prepared in the compositions shown in Table 3. In Preparation Examples 10 to 12, in which 4,4-dicyclohexylmethane diisocyanate and isophoronediamine were used, the polyurethane solutions were prepared in the same manner as in Preparation Examples 5 to 8. The Solid content and viscosity at 25°C of the solutions were 25 wt% and 20,000 cps in Preparation Example 10, 20 wt% and 23,000 cps in Preparation Example 11, and 20 wt% and 18,000 cps in Preparation Example 12.

In Preparation Example 13, a urethane prepolymer was obtained by reacting 4,4'-diphenylmethane diisocyanate and polyol 13 in a flask under a dry nitrogen atmosphere at 80°C for four hours. Then, a chain extension reaction of the above prepolymer was carried out in dimethylformamide at 80°C for six hours using 1,4-butanediol as a chain extender in the presence of 100 ppm of dibutyltin dilaurate. The solid content was 25 wt% and the viscosity at 25°C was 19,000 cps.

The formation of the polyurethane film and property test were carried out in the same manner as in Preparation Examples 5 to 8.

The properties of the polyurethane films of Preparation Examples 10 and 11 are shown in Table 4. Table 3 Number of preparation examples (comparative examples) Composition of polyurethanes (parts by weight) Polyol 4,4'-dicyclohexylmethane diisocyanate 4,4'-diphenylmethane diisocyanate Isophoronediamine 1,4-butanediol Note: Polytetramethylene ether glycol with a number average molecular weight of 2000 (sold by Mitsubishi Kasei Corporation) Table 4 Number of production examples (stabilizer added) EO content in polyurethane (wt.%) Dimensional increase due to water absorption (%) Water vapor permeability (g/m² x 24 hours) Film thickness 10 um Mechanical properties 100% modulus (kg/cm²) Tensile strength (kg/cm²) Elongation (%) Oxidation resistance 100% modulus retention (%) Hydrolysis resistance Tensile strength retention (%)

Examples 1 to 6

A laminate sheet of a collagen sheet and a polyurethane film was prepared as follows. A uniform foaming solution was prepared by stirring a solution containing 1 wt% of atelocollagen and adjusted to pH 4 with hydrochloric acid in a homogenizer at a speed of 1500 rpm for 5 minutes.

It was flow-cast to a thickness of 1 to 2 mm. Then, the atelocollagen solution was neutralized by leaving it in an ammonia atmosphere for 30 minutes to gelatinize. A spongy collagen sheet was then obtained by freeze-drying the atelocollagen gel in a freeze dryer at -30ºC. This collagen sheet was made water-insoluble by cross-linking with UV irradiation. A small amount of methanol was absorbed into the collagen sheet. Then, a laminate sheet of the spongy collagen sheet and the polyurethane film was obtained by laminating the collagen sheet with a polyurethane film having a thickness of 30 µm obtained in Preparation Examples 5 to 7, 10, 11 or 13 and drying it. A porous laminate sheet was obtained by forming holes with a frog.

The layer was sterilized with gaseous ethylene oxide and tested.

A wound (diameter: 35 mm) corresponding to a full-thickness skin defect was surgically created on the abdominal part of a rat (SP rat, 6 to 8 weeks old), and a 0.4 mm diameter stainless steel ring was sewn into it (16 stitches). The laminate layer obtained above was applied to the ring, a moisture-retaining cotton ball and sanitary cotton were placed on top and then bandaged with an elastic band. The biocompatibility and regeneration of the dermis were histologically checked after one week and two weeks. The effect of the laminate sheet was also evaluated. These results are shown in Table 5. The healing effect is good for all the laminate sheets and the laminate sheet of the present invention was found to be suitable for a wound dressing.

Example 7

A laminate sheet of an alginic acid sheet and a polyurethane film was prepared as follows. A uniform forming dispersion was obtained by dispersing sodium alginate (sold by Kimitsu Kagaku Industry Co., Ltd.) in water at a concentration of 2% and stirring the dispersion using a homogenizer at a speed of 1500 rpm for 5 minutes.

It was flow-molded to a thickness of 1 to 2 mm, and a sponge-like sheet of sodium alginate was obtained by freeze-drying at -80°C. Then, after spraying methanol onto the sodium alginate sheet, the polyurethane film having a thickness of 30 µm obtained in Preparation Example 10 was laminated thereon and dried to obtain a laminate sheet. A porous laminate sheet was obtained by making holes with a frog. This was tested after sterilization treatment by gaseous ethylene oxide. The applicability of this laminate sheet as a wound dressing was evaluated by an experiment similar to that in Examples 1 to 6. As is clear from the results in Table 5, the laminate sheet was found to be effective as a wound dressing in the same manner as in the case of Examples 1 to 6.

Example 8

A laminate layer of a collagen chitosan and a polyurethane film was prepared as follows.

In 0.5 l of a 2% acetic acid solution, 9 g of N-succinylchitosan with a degree of succinylation of 50% and 1 g of atelocollagen were dissolved; 1 l of methanol was then added to the solution.

12 g of acetic anhydride was added to the aqueous methanol-acetic acid solution containing N-succinylchitosan and atelocollagen, mixed well and left at room temperature for 10 hours. The solution was thoroughly washed with water to remove acetic acid and methanol, thereby obtaining 180 g of a hydrated gel of acetylated chitosan-collagen.

The hydrated gel thus prepared was immersed in 3 L of methanol, quick-frozen by adding dry ice, and then freeze-dried in vacuum to obtain 10 g of an acetylated chitosan-collagen sponge. The sponge was cut into a piece of 2 mm thickness, followed by irradiation with 5 Mrad of gamma rays to crosslink the acetylated chitosan-collagen. The crosslinked sponge was immersed in methanol, and then, after removing most of the methanol, a polyurethane film of 25 µm thickness obtained in Preparation Example 7 was laminated thereon and air-dried at room temperature.

The resulting acetylated chitosan-collagen laminate was provided with holes with a diameter of 0.3 mm (10 holes per 1 cm² area) using a frog.

The porous laminate layer was sterilized with gaseous ethylene oxide and tested by the same tests as in Examples 1 to 7.

The results are shown in Table 5. Table 5 No. of examples Polyurethane film EO content in polyurethane (weight) Properties of polyurethane films Dimensional increase due to water absorption (%) Water vapor permeability (g/m²x24hr) Layer made of biopolymer material Healing effect in rats Manufacturing example Collagen layer good Aliginic acid layer Chitosan collagen layer

Comparative examples 1 to 2

Two porous laminate sheets were obtained from the sponge-like collagen sheet and the polyurethane films having a thickness of 30 µm obtained in Preparation Examples 8 and 12 in the same manner as in Examples 1 to 6. The applicability of these laminate sheets as a wound dressing was examined. The results are shown in Table 6.

In Comparative Example 1, the water vapor permeability of the polyurethane film was high, but the adhesion between the laminate sheet and the wound was poor due to swelling of the film due to water absorption. In Comparative Example 2, a curing effect was recognized, but the extent of the effect was insufficient compared with Examples 1 to 6. This was because the water vapor permeability of the polyurethane film was low. Table 6 No. of comparative examples Polyurethane film EO content in polyurethane (wt.%) Properties of urethane films Layer made of biopolymer material Healing effect Dimensional increase of water absorption (%) Water vapor permeability (g/m²x24 h) Manufacturing example 8 Collagen layer poor adhesion due to swelling, poor Effect present, but worse than in examples

Example 9

A laminate layer of a polyurethane film and a collagen layer containing an antibacterial agent was prepared as follows.

A foaming dispersion was prepared by adding silver sulfadiazine to a 1% atelocollagen solution adjusted to pH 4 with hydrochloric acid in such an amount that the concentration of silver sulfadiazine was 1500 ppm and then stirring the solution using a homogenizer at a speed of 1500 rpm for 5 minutes.

It was flow cast to a thickness of 1 to 2 mm. Then, the atelocollagen solution was neutralized by leaving it in an ammonia atmosphere for 30 minutes to gelatinize. The atelocollagen gel was freeze-dried in a freeze dryer at -30ºC to obtain a sponge-like collagen layer. The collagen layer was made water-insoluble by cross-linking it with UV irradiation.

A small amount of methanol was absorbed in the collagen sheet. Then, the polyurethane film having a thickness of 30 µm obtained in Preparation Example 5 was laminated on the collagen sheet so that a laminate sheet of the polyurethane film and the collagen sheet containing an antibacterial agent was obtained. A porous laminate sheet was obtained by forming holes using a frog.

After sterilization with gaseous ethylene oxide, the resulting leaf was tested as follows:

Pseudomonas aeruginosa was inoculated into an agar culture medium at a density of 10⁷ P.a/cm². Then, the sterilized laminate sheet was placed on top and the number of bacteria under the sheet was measured after one day. For comparison, the same experiment was repeated using a chitin nonwoven fabric and pig skin.

After one day, Pseudomonas aeroginosa under the layer containing an antibacterial agent was completely disinfected, whereas under the chitin nonwoven fabric and the pig skin, Pseudomonas aeroginosa proliferated and the number of bacteria was 10⁹ P.a/cm².

Claims (10)

1. A wound dressing comprising a layer of a biopolymeric material and a polyurethane resin film having a water vapor permeability of 2,000 g/m2 x 24 hours or more, wherein the polyurethane resin is obtainable by reacting a diisocyanate and a random copolymer of tetrahydrofuran and ethylene oxide to prepare a urethane prepolymer, and extending the molecular chain of this prepolymer using a chain extender, wherein the random copolymer contains 20 to 80 wt% ethylene oxide units in its molecular chain and has a number average molecular weight of 800 to 3,000. 2. Wound dressing according to claim 1, characterized in that the polyurethane resin film or the layer of biopolymer material contains an antibacterial agent. 3. Wound dressing according to claim 1 or 2, characterized in that the random copolymer has 30 to 70% by weight of ethylene oxide units in its molecular chain. 4. A wound dressing according to claim 1, 2 or 3, characterized in that the number average molecular weight of the random copolymer is 1000 to 2500. 5. Wound dressing according to one of the preceding claims, characterized in that the diisocyanate is an alicyclic diisocyanate. 6. Wound dressing according to claim 5, characterized in that the alicyclic diisocyanate is selected from isophorone diisocyanate, 4,4'-dicyclohexylmethane diisocyanate, 1,4-cyclohexylene diisocyanate and hydrogenated tolylene diisocyanate. 7. Wound dressing according to one of the preceding claims, characterized in that the chain extender is an alicyclic diamine. 8. Wound dressing according to claim 7, characterized in that the alicyclic diamine is selected from isophoronediamine, 4,4'-dicyclohexylmethanediamine, 3,3'-dimethyl-4,4'-dicyclohexylmethanediamine and 1,4-cyclohexylenediamine. 9. Wound dressing according to one of the preceding claims, characterized in that the thickness of the polyurethane resin film is 10 to 80 µm amounts. 10. A wound dressing according to any one of the preceding claims, characterized in that the 100% modulus of the polyurethane resin film is 20 kg/cm² or more.